This invention relates to the use of the tricyclic antidepressants to produce local long-acting relief of different varieties of pain.
To provide a better understanding of the invention it is necessary to distinguish between the two terms analgesia and anesthesia. Analgesia is defined as a condition in which nociceptive stimuli are sensed but are not interpreted as pain. Anesthesia is a state characterized by total loss of sensation, the result of pharmacologic depression of nerve function. Thus, analgesia does not produce anesthesia whereas anesthesia produces analgesia.
In general, pain is associated with a known tissue pathology (e.g., cancer pain, arthritic pain), inflammation, or injury to a body tissue (e.g., surgery). Neuropathic pain is thought to be a consequence of damage to peripheral nerves or to regions of the central nervous system. Neuropathic pain can present as an acute pain but frequently occurs as a form of chronic pain.
The use of long-acting local anesthetics that elicit complete neural blockage for more than several hours is frequently desirable in the management of acute and chronic pain. Pain relief research during the last two decades has focused on the identification of new local anesthetics to produce analgesia of long duration with minimal impairment of autonomic function and low toxicity. One of the best known xe2x80x9clong-actingxe2x80x9d local anesthetics developed to date, bupivacaine, reportedly blocks major nerve block for three to twelve hours. Unfortunately, bupivacaine is also highly cardiotoxic. The development of alternative xe2x80x9clong-actingxe2x80x9d local anesthetics met limited success.
Pain relief research also has focussed on the identification of new neurolytic agents for the treatment of chronic pain and intractable cancer pain. Historically, spinal opiate administration, surgical intervention, or both have been used to alleviate chronic and intractable cancer pain. When these methods fail to provide insufficient pain relief, phenol or absolute alcohol reportedly have been used as neurolytic agents to destroy the pathogenic nerve regions that are responsible for pain manifestation. However, these agents exert only weak local anesthetic effects and, accordingly, have been difficult to administer to alert patients without inducing additional pain. To date, a long-acting local anesthetic with no major side effects has not been available for the treatment of acute and chronic pain.
In view of the foregoing limitations of the existing local anesthetics to prolong the duration of anesthesia, a need still exists for useful long-acting local anesthetics for pain management. Preferably such local long-acting anesthetics also will exhibit reversible effects. Such drugs would be useful and desirable, for example, in postoperative analgesia, and for treating acute and chronic pain. Preferably, such agents would have sufficient potency to permit administration of a single, relatively low dosage of the agent, thereby minimizing the likelihood of side effects that have been attributed to the existing local long-acting anesthetic agents.
Tricyclic antidepressants are frequently used as analgesics in pain management but only when administered systemically. Among them, amitriptyline has been used orally for the analgesic therapy of chronic pain. Amitriptyline""s sites of action are both central and peripheral. Despite the numerous reports on amitriptyline""s analgesic effect on reducing pain when administered systemically, the exact mechanism of this effect remains unknown. To our knowledge, tricyclic antidepressants have not been used as local analgesics. Likewise, they have not been used at all as anesthetics either locally or systemically.
The invention involves in one respect the surprising discovery that tricyclic antidepressants act as long-acting local anesthetics and analgesics that are useful for alleviating pain. These tricyclic antidepressants exhibit unexpected anesthetic and analgesic properties compared to related compounds that previously have been used for pain management. The availability of compounds with strong local long-acting anesthetic properties, such as that of tricyclic antidepressants described herein, are advantageous over the existing compounds for pain management because conventional neurolytic agents typically exert only weak local anesthetic effects which are of short duration and produce irreversible damage to the nerves.
According to one aspect of the invention, a method for inducing local anesthesia in a subject is provided. The method involves administering locally to a subject in need of such a treatment an effective amount of a tricyclic antidepressant in an amount effective to block sensory and motor functions of a nerve(s) at the site of administration of the tricyclic antidepressant. The tricyclic antidepressant is selected from those described in the formulas below.
In one embodiment, the tricyclic antidepressant is amitriptyline or one of its analogues. Analogues of amytripyline include quaternary and tertiary analogues. Examples of quaternary amytripyline analogues include but are not limited to N-phenyl-propyl amitriptyline bromide, N-phenyl-ethyl amitriptyline bromide, or N-phenyl-methyl amitriptyline bromide. Tertiary amitriptyline analogues include but are not limited to N-phenyl-propyl nortriptyline bromide, N-phenyl-ethyl nortriptyline bromide, or N-phenyl-methyl nortriptyline bromide. A preferred quaternary analogue is N-phenyl-ethyl amitriptyline bromide.
The tricyclic antidepressant is administered in a therapeutically effective amount sufficient to induce anesthesia in a subject at the site of administration for at least 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, or 96 hours.
The compounds of the invention are useful when administered locally in treating all categories of pain, whether acute or chronic, local or general. The subject according to the invention can be experiencing or at risk of experiencing any of the forgoing categories of pain. Examples of different kinds of pain are described in the Detailed Description.
The compounds of the invention can be administered to sites well known by those of ordinary skill in the art to be appropriate for interfering with the nerve(s) propagating such pain.
In one embodiment of the invention, the tricyclic antidepressant is administered in the lower back to alleviate pain. In another embodiment, the tricyclic antidepressant is administered to alleviate pain propagated by the sciatic nerve.
The preferred mode of administration is local administration such as by injection, intramuscularly, subcutaneously, dermally, or intradermally by inhalation or by local application topically such as in a lotion or a patch.
In yet another aspect of the invention, a method for inducing local analgesia in a subject is provided. The method involves administering locally to a subject in need of such a treatment an effective amount of a tricyclic antidepressant in an amount effective to block sensory function of a nerve(s) at the site of administration of the tricyclic antidepressant. The tricyclic antidepressant is selected from those described in the formulas below.
In one embodiment, the tricyclic antidepressant is amitriptyline or one of its analogues. Analogues of amytripyline are quaternary and tertiary analogues. Examples of quaternary amytripyline analogues include but are not limited to N-phenyl-propyl amitriptyline bromide, N-phenyl-ethyl amitriptyline bromide, or N-phenyl-methyl amitriptyline bromide. Tertiary amitriptyline analogues include but are not limited to N-phenyl -propyl nortriptyline bromide, N-phenyl-ethyl nortriptyline bromide, or N-phenyl-methyl nortriptyline bromide. A preferred analogue is N-phenyl-ethyl amitriptyline bromide.
The tricyclic antidepressant is administered in a therapeutically effective amount sufficient to induce analgesia in a subject at the site of administration for at least 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, or 96 hours.
The compounds of the invention are useful when administered locally in treating all categories of pain, whether acute or chronic, local or general. The subject according to the invention can be experiencing or at risk of experiencing any of the forgoing categories of pain. Examples of the different kinds of pain are described in the Detailed Description.
The compounds of the invention can be administered to sites well known by those of ordinary skill in the art to be appropriate for interfering with the nerve(s) propagating such pain.
In one embodiment of the invention, the tricyclic antidepressant is administered in the lower back to alleviate pain. In another embodiment, the tricyclic antidepressant is administered to alleviate pain propagated by the sciatic nerve.
The preferred mode of administration is local administration such as by injection, intramuscularly, subcutaneously, dermally, or intradermally, by inhalation or by local application topically such as in a lotion or a patch.
In some embodiments the tricyclic antidepressants are: amytriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine, or one of their analogues including quaternary and tertiary.
In some embodiments, the tricyclic antidepressant is an analogue of any number of well-known trycyclic antidepressants modified at the nitrogen which forms part of the carbon chain attached to the tricyclic moiety. Preferred are amphipathic derivatives of tricyclic antidepressants. In important embodiments, the derivatives are quaternary analogues. In other embodiments, the derivatives are tertiary analogues.
It is preferred that the analogues of the tricyclic antidepressants be such that the hydrophobicity of the tricyclic antidepressant is increased. It is also preferred that the hydrophobicity-increasing moiety be a moiety which would not insert within and be captured by a lipid membrane (e.g., moieties that are long, unbranched alkyls such as C6 or greater chains).
Preferred quaternary or tertiary amine derivatives of the tricyclic antidepressants are cyclic derivatives such as, a phenyl-methyl, phenyl-ethyl, phenyl-propyl, or phenyl-butyl derivative. The preferred compound is: 
Other important tricyclic antidepressants which can be derivatized as described above include: 
An important subclass of the tricyclic antidepressants can be represented by the following formula: 
wherein
R1 equals Cxe2x80x94C, Cxe2x80x94O or Cxe2x95x90C
xcex3-xcex2 equals Cxe2x95x90C, Nxe2x80x94C or CHxe2x80x94C
n equals 1, 2, 3, 4, 5, or 6
R2 equals H or H2 
R3 equals H or CH3 or nothing
R4 equals H or R6 
R5 equals H or R6 
R6 equals (C1-C8) alkyl, (C1-C8) substituted alkyl, (C1-C8) alkenyl, (C1-C8) substituted alkenyl, (C1-C8) alkynyl, (C1-C8) substituted alkynyl (wherein the subtituents can be (C1-C4) alkyl, (C1-C4) substituted alkyl, (C1-C4) alkenyl, (C1-C4) substituted alkenyl, (C1-C4) alkynyl, (C1-C4) substituted alkynyl), or R6 is nothing,
R7 equals H or Cl
R8 equals H or Cl
R9 equals H or Cl,
and wherein when R1 equals Cxe2x95x90C, at least one of R4, R5, and R6 is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbons in length.
In one important embodiment, when R1 equals Cxe2x80x94C, xcex3-xcex2 equals Cxe2x95x90C, and n equals 1, at least one of R4, R5, and R6 is not CH3 (when R6 is present) and at least one of R4 and R5 is not CH3 (when R6 is not present).
In one important embodiment R1 equals Cxe2x80x94C. In another important embodiment R1 equals Cxe2x80x94O. In another important embodiment R1 equals Cxe2x95x90C. In another important embodiment xcex3-xcex2equals Nxe2x80x94C. In another important embodiment n equals 1. In still another important embodiment n equals 2. In yet another embodiment, at least one of R4, R5, and R6 contains 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbons. Important compounds of this embodiment have at least one of R4, R5, and R6 containing 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbons. Other important compounds of this embodiment have at least one of R4, R5, and R6 containing 6, 7, 8, 9, 10, 11 or 12 carbons. Still other important compounds of this embodiment include quaternary and tertiary amine derivatives. Other important compounds of this embodiment have R1 equals Cxe2x80x94C. In still other important embodiments, R7, R8, and R9 are H.
According to another aspect of the invention, compositions of matter are provided. The compositions of matter are quaternary amine derivatives of tricyclic antidepressants, such as those described above. Preferred derivatives are those described above.
The invention also involves pharmaceutical preparations comprising:
an effective amount of any one of the foregoing compositions of matter, and
a pharmaceutically-acceptable carrier.
The invention further involves pharmaceutical preparations comprising:
a tricyclic antidepressant or analogue thereof,
an anti-inflammatory agent, and
a pharmaceutically-acceptable carrier.
The invention also involves pharmaceutical preparations comprising:
a tricyclic antidepressant or analogue thereof in a topical formulation or aerosol formulation, such as a cream, lotion, ointment, propellant, patch, and the like.
These and other aspects of the invention will be described in greater detail below.
These and other aspects of the invention, as well as various advantages and utilities will be more apparent with reference to the drawings and the detailed description of the preferred embodiments.
All references, patents, and patent publications identified in this document are incorporated in their entirety herein by reference.